primary biliary cholangitis
TRANSCRIPT
Primary Biliary Cholangitis
Miss Eleri Lougher
MSc. IPresc. MRPharmS
Lead Pharmacist: Birmingham Hepatitis C / PBC ODN
PBC Presentation
The classical phenotype➢ 90% women
➢ 75% of women above the age of 50 yrs
➢ Itching and fatigue
➢ High cholesterol
➢ Often have a history of smoking
Emerging recognition1
➢ Asymptomatic
➢ 25% between 25 – 49 yrs at diagnosis
➢ 10% men
Carbone et al. Gastro 2013
PBC Diagnosis
Chronically elevated serum ALP
➢ Exclusion of large bile duct obstruction
➢ e.g. stones in bile duct, PSC
+ve anti-mitochondrial antibody (AMA) in 95%
➢ Other auto-antibodies➢ Specific ANA: Anti-sp100, anti-gp210
➢ Raised IgM levels
➢ Liver biopsy rarely needed
PBC Treatment
Who to treat➢ All patients with elevated ALP
Medication and dosing➢ Ursodeoxycholic acid (UDCA) at 13 – 15 mg/kg/d
➢ Obeticholic acid dose as per SPC & NICE ta443
Goals of therapy
➢ Attain biochemical response
➢ Prevent disease progression
➢ Manage associated symptoms
➢ Maintain a Quality of Life
PBC: pearls
➢ Overall, 2/3 of pts. respond to UDCA
➢ Non-responders most often:
➢ Men
➢ 50% of women < 50 yrs. at diagnosis
➢ Patients who do badly
➢ Biochemical non-responders
➢ Fibroscore rising year on-year / score >9 kPa
➢ Elevated AST / platelet ratio index
Trivedi, et al. Hepatology 2016
Miss JB
➢ 46 years old; married woman; full-time employment
➢PBC diagnosed aged 39 years old
➢AMA-positive
➢ AMA-M2, sp100, PML, multiple nuclear dot (MND) pattern (1 in 1600)
➢Symptomatic: fatigue
➢Non-smoker; no EtOH; no relevant family history
➢Cirrhotic (USS) – Under HCC Surveillance
How do you risk stratify your patients?
Dichotomous biochemical criteria?
➢ Toronto
➢ Barcelona
➢ Paris I
➢ Paris II
➢ Rochester
➢ Ehime
With continuous scoring?
➢ GLOBE
➢ UK PBC
Stage information?
➢ Child–Pugh score
➢ Rotterdam criteria
Miss JB
PBC GLOBE score:
GLOBE score: -0.03
Threshold: -0.52
Liver transplant-free survival
GLOBE score Mean survival of
age- and sex-
matched patients
≤45 years
3-year 96.6% 99.5%
5-year 94.0% 99.2%
10-year 84.7% 98.0%
15-year 74.3% 96.2%
Miss JB
Clinical and lab criteria Points*
1 2 3
Encephalopathy None Mild to moderate
(grade 1 or 2)
Severe
(grade 3 or 4)
Ascites None Mild to moderate
(diuretic
responsive)
Severe
(diuretic refractory)
Bilirubin (mg/dL) <2 2–3 >3
Albumin (g/dL) >3.5 2.8–3.5 <2.8
Prothrombin time
Seconds prolonged
International normalised
ratio
<4
<1.7
4–6
1.7–2.3
>6
>2.3
Child–Turcotte–Pugh Class obtained by adding score for each parameter (total
points)
Class A = 5 to 6 points (least sever liver disease)
Class B = 7 to 9 points (moderately severe liver disease)
Class C = 10 to 15 points (most severe liver disease)
May 2012
12 months post UDCA initiation:
→ UDCA 750mg daily
May 2012
result
Compared to
ULNULN
ALP (U/L) 1200 10.20 x ULN 117
GGT (U/L) 1500 50 x ULN 30
Post-initiation
Result (12
months)
Compared to
ULNULN
ALP (U/L) 300 2.56 x ULN 117
GGT (U/L) 270 9 x ULN 30
July 2014
➢ Optimised to UDCA 1000mg daily
➢ (weight-base dose)
➢ Adcal D3
ALP alkaline phosphatase; PLATS platelets; AST alanine aminotransferase
Jul 2014
Result
Compared to
ULNULN
ALP (U/L) 439 3.75 x ULN 117
AST (U/L) 88 1.83 x ULN 48
Bilirubin
(µmol/L)9 0.53 x ULN 17
PLATS
(x109/L)133 < ULN 450
December 2014Dec 2014
Result
Compared to
ULNULN
ALP (U/L) 367 3.14 x ULN 117
AST (U/L) 70 1.46 x ULN 48
Bilirubin
(µmol/L)8 0.47 x ULN 17
PLATS
(x109/L)- - 450
88
9
AST
439
ALP
367
70
8
Jul-14
Bilirubin
ALP alkaline phosphatase; PLATS platelets; AST alanine aminotransferase
Dec-14
➢ 3 columns of grade 1 varices
➢ Primary prophylaxis with carvedilol
February 2015Feb 2015
Result
Compared to
ULNULN
ALP (U/L) 369 3.15 x ULN 117
AST (U/L) 58 1.21 x ULN 48
Bilirubin
(µmol/L)7 0.41 x ULN 17
PLATS
(x109/L)132 < ULN 450
88
9
AST
439ALP
369367
70 58
87
Jul-14 Dec-14
Se
rum
liv
er
tests
(s
ee
ta
ble
)
Bilirubin
Feb-15
ALP alkaline phosphatase; PLATS platelets; AST alanine aminotransferase
➢ Optimised carvedilol to 12.5mg OD
October 2015Oct 2015
Result
Compared to
ULNULN
ALP (U/L) 355 3.03 x ULN 117
AST (U/L) 68 1.42 x ULN 48
Bilirubin
(µmol/L)12 0.71 x ULN 17
PLATS
(x109/L)107 < ULN 450
88
9
AST
439ALP
369367355
70 58 68
87
12
Jul-14 Dec-14 Feb-15
Se
rum
liv
er
tests
(s
ee
ta
ble
)
Bilirubin
Oct-15
ALP alkaline phosphatase; PLATS platelets; AST alanine aminotransferase
➢ Symptomatic Pruritus
Symptoms
Pruritus
1st line: Colestyramine (sticks to everything!)
➢ TAKE 6 HRS. BEFORE AND 1 HR. AFTER OTHER PILLS
2nd line: Rifampicin
Caution
➢ Multiple interactions
➢ 20-30% can experience deteriorating liver enzymes (monitor 2-4 weekly)
➢ Vitamin K supplementation
Beuers et al. J Hepatol 2015
February 2017
➢ Screen fail for COBALT trial
➢ (ALP <3 x ULN)
Feb 2017
Result
Compared to
ULNULN
ALP (U/L) 332 2.84 x ULN 117
AST (U/L) - - 48
Bilirubin
(µmol/L)17 1 x ULN 17
PLATS
(x109/L)102 < ULN 450
88
9
AST
439ALP
369367
332355
70 58 68
87
1412
Jul-14 Dec-14 Feb-15 Oct-15
Se
rum
liv
er
tests
(s
ee
ta
ble
)
Bilirubin
Feb-17
ALP alkaline phosphatase; PLATS platelets; AST alanine aminotransferase
August 2017Aug 2017
Result
Compared to
ULNULN
ALP (U/L) 292 2.50 x ULN 117
AST (U/L) 86 1.79 x ULN 48
Bilirubin
(µmol/L)16 0.94 x ULN 17
PLATS
(x109/L)95 < ULN 450
88
9
AST
439ALP
369367
332
292
355
70 58 6886
87
1614
12
Jul-14 Dec-14 Feb-15 Oct-15 Feb-17
Se
rum
liv
er
tests
(s
ee
ta
ble
)
Bilirubin
Aug-17
ALP alkaline phosphatase; PLATS platelets; AST alanine aminotransferase
Considering her blood work, what would
you do now?
➢ Repeat serum assessments
➢ Adjust UDCA dosing
➢ Liver biopsy
➢ Consider second-line treatment options
August 2017
➢ Inadequate response to UDCA
➢ MDT referral
Aug 2017
Result
Compared to
ULNULN
ALP (U/L) 292 2.50 x ULN 117
AST (U/L) 86 1.79 x ULN 48
Bilirubin
(µmol/L)16 0.94 x ULN 17
PLATS
(x109/L)95 < ULN 450
88
9
AST
439ALP
369367
332
292
355
70 58 6886
87
1614
12
Jul-14 Dec-14 Feb-15 Oct-15 Feb-17
Se
rum
liv
er
tests
(s
ee
ta
ble
)
Bilirubin
Aug-17
ALP alkaline phosphatase; PLATS platelets; AST alanine aminotransferase
August 2017: PBC MDT
➢ Child–Pugh A (5) cirrhotic with portal hypertension and pruritus
➢ Started 5mg three times/week
➢ Some increased itch; tolerable; took cholestyramine
➢ Up to 5mg daily November 2017
➢ Itch settled to baseline
88
9
AST
439ALP
369367
332
292
217
355
70 58 6886 60
87 12
1614
12
Jul-14 Dec-14 Feb-15 Oct-15 Feb-17 Aug-17 Feb-18
Se
rum
liv
er
tests
(s
ee
ta
ble
)
OCA initiated
Feb 2018
Result
Compared to
ULNULN
ALP (U/L) 217 1.85 x ULN 117
AST (U/L) 60 1.25 x ULN 48
Bilirubin
(µmol/L)12 0.71 x ULN 17
PLATS
(x109/L)97 < ULN 450
Bilirubin
ALP alkaline phosphatase; PLATS platelets; AST alanine aminotransferase
➢ Biochemical response on OCA
February 2018
Clinical Course Summary
➢ May 2012: UDCA 750mg daily
➢ July 2014: optimised to UDCA 1000mg daily (weight-based
dose); Adcal D3
➢ December 2014: 3 columns of grade 1 varices; primary
prophylaxis with carvedilol
➢ February 2015: optimised carvedilol to 12.5mg OD
➢ October 2015: pruritus
➢ February 2017: screen fail for COBALT trial (ALP <3 x ULN)
➢ August 2017: inadequate response to UDCA & OCA initiation
➢ February 2018: OCA dose increased to 5mg/10mg alt days
with the aim of increasing further to 10mg daily.
Key Points
➢ Young onset PBC
➢ Insufficient response to UDCA
➢ Optimise UDCA dose to 12-15mg/kg/d
➢ Reduced pill burden with 500 mg tablet
➢ Tablets vs. capsules (latter contain gelatin!)
➢ Symptomatic disease with cirrhosis
➢ HCC surveillance
➢ Timely implementation of second-line treatment
➢ Discontinuation if no response?
Child-Pugh BOR
Child-Pugh COR
Decompensated Cirrhosis
OCA 5mg once weekly
OCA 5mg twice weekly
OCA 10mg twice weekly
3 MonthsIf no adequate reduction in
ALP and/or Bilirubin
If tolerating treatment
Starting Dose
Maximum Dose
OCALIVA® Dosing
Thank You…….
Any Questions?